This formulary decision guide was initiated, funded, and reviewed by Boehringer Ingelheim Limited and Lilly Diabetes Alliance. The format was developed by Guidelines in Practice.

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Key points on this medicine

Final version_Jardiance FDG update

Jardiance:

  • is a once-daily SGLT2 inhibitor that improves glycaemic control in adult patients with type 2 diabetes mellitus1–3
  • has a secondary benefit of weight loss versus placebo4*
  • provides a reduction in major cardiovascular events versus placebo in patients with type 2 diabetes and established CV disease.5*

*Jardiance is not indicated for weight loss, reduction of CV risk, or the treatment of heart failure
Nonfatal MI, nonfatal stroke and CV death

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Drug name

Jardiance® (empagliflozin) film-coated tablets

Indication

  • Jardiance is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise:1
    • as monotherapy when metformin is considered inappropriate due to intolerance
    • in addition to other medicinal products for the treatment of diabetes
  • For study results with respect to treatment combinations, effects on glycaemic control and CV events, and the populations studied, refer to the SPC.1

Dosage and administration

  • Empagliflozin tablets are available in two strengths, 10 mg and 25 mg, and can be taken with or without food1
  • The starting dose is 10 mg empagliflozin once daily for monotherapy and add-on combination therapy with other medicinal products for the treatment of diabetes1
  • In patients tolerating empagliflozin 10 mg once daily who have an eGFR ≥60 ml/min/1.73 m2 and need tighter glycaemic control, the dose can be increased to 25 mg once daily1
  • When used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia1
  • No dose adjustment is required for patients with an eGFR ≥60 ml/min/1.73 m2
    or CrCl ≥60 ml/min1
  • For patients with renal impairment:1
    • treatment should not be initiated if eGFR <60 ml/min/1.73 m2
    • who are able to tolerate empagliflozin and whose eGFR falls persistently <60 ml/min/1.73 m2, the dose of empagliflozin should be adjusted to or maintained at 10 mg once daily
    • empagliflozin should be discontinued when eGFR is persistently <45 ml/min/1.73 m2
  • Empagliflozin is not recommended for use in patients with severe hepatic impairment.1

Mode of action

  • Empagliflozin improves glycaemic control in patients with type 2 diabetes by reducing renal glucose reabsorption1
  • In patients with type 2 diabetes empagliflozin increased urinary glucose excretion to approximately 78 g/day, and thus empagliflozin has been associated with weight loss1*
  • The MOA is independent of beta cell function and insulin pathway, contributing to a low risk of hypoglycaemia.1

*Jardiance is not indicated for weight loss, reduction of CV risk, or the treatment of heart failure

Evidence for use

Glycaemic benefits

  • Empagliflozin (n=224 for empagliflozin 10 mg and n=224 for empagliflozin 25 mg) resulted in a statistically significant (p<0.0001) difference in HbA1c compared with placebo (n=228) at 24 weeks6
  • 24-week clinical trials found that empagliflozin as add‑on to metformin or metformin plus a sulphonlyurea significantly improved glycaemic control versus the comparator arms2,3

Secondary benefit of weight loss*

  • A 104-week phase III study found that treatment with 25 mg empagliflozin resulted in a significant and sustained reduction in weight, with an adjusted mean change from baseline in bodyweight of −3.12 kg versus treatment with glimepiride, which showed an increase of +1.34 kg (difference of −4.46 kg (97.5% CI −4.87 to −4.05, p<0.0001).4

Cardiovascular outcomes*

  • EMPA-REG OUTCOMES was a randomised, double blind placebo‑controlled safety trial of patients with type 2 diabetes and established CV disease (n=7020) comparing empagliflozin 10 mg and 25 mg with placebo plus standard of care, which found that:1,5,7,8
    • empagliflozin was superior in reducing the primary combined endpoint of CV death, non-fatal MI, or non-fatal stroke (pooled figure, ARR 1.6%, RRR 14%, HR 0.86; 95% CI 0.74, 0.99, NNT 61, p=0.038)
    • empagliflozin showed a 38% RRR in CV death on top of standard of care versus placebo (pooled figure, ARR 2.2%, HR 0.62; 95% CI 0.49, 0.77, NNT 45, p<0.001)
    • there was a 35% RRR in hospitalisation for heart failure in the pooled empagliflozin group on top of standard of care versus placebo (ARR 1.4 %, HR 0.65; 95% CI 0.50, 0.85, p=0.002)
    • empagliflozin showed a 32% RRR in death by any cause (pooled figure, ARR 2.6%, HR 0.68; 95% CI 0.57, 0.82, NNT 38, p<0.001).

*Jardiance is not indicated for weight loss, reduction of CV risk, or the treatment of heart failure

Guidance recommendations

  • NICE have published recommendations on the use of empagliflozin for the treatment of type 2 diabetes (TA336 and TA390), which can be accessed via the NICE website9,10
  • SIGN has published the following advice:11
    • in individuals with type 2 diabetes and established CV disease, SGLT2 inhibitors with proven CV benefit (currently empagliflozin and canagliflozin) should be considered
  • The ADA/EASD consensus report recommends to assess the presence of CV disease in patients with T2DM on metformin. In patients with T2DM and established atherosclerotic CV disease, SGLT2 inhibitors with proven CV benefit are recommended.12

Budgetary implications

  • A 28-pack of tablets (10 mg and 25 mg) costs £36.59 and is priced at parity per tablet with canagliflozin (100 mg and 300 mg) and dapagliflozin (5 mg and 10 mg).13

Safety profile

  • The overall incidence of adverse events in patients treated with empagliflozin was similar to placebo1
  • The most frequently reported adverse event was hypoglycaemia when used with sulphonylurea or insulin1
  • Genital infections and UTI are common side-effects1
  • In patients aged ≥75 years, an increased risk for volume depletion should be taken into account. In patients aged ≥85 years, initiation of empagliflozin is not recommended1
  • An increase in cases of lower limb amputation (primarily of the toe) has been observed in CANVAS and CANVAS-R, two clinical studies for canagliflozin. This signal has not been shown in the empagliflozin trial programme1,14
  • Empagliflozin should not be used in patients with type 1 diabetes or for the treatment of DKA. If DKA is suspected or diagnosed, empagliflozin should be discontinued immediately1
  • Cases of Fournier’s gangrene have been reported in patients taking SGLT2 inhibitors; if suspected, empagliflozin should be discontinued and prompt treatment should be initiated1
  • Refer to SPC for adverse effects and contraindications.1

Abbreviations

SGLT2=sodium glucose co-transporter 2; CV=cardiovascular; MI=myocardial infarction; SPC=summary of product characteristics; eGFR=estimated glomerular filtration rate; CrCl=creatinine clearance; MOA=mode of action; HbA1c =glycated haemoglobin; CI=confidence interval; ARR=absolute risk reduction; RRR=relative risk reduction; HR=hazard ratio; SIGN=Scottish Intercollegiate Guidelines Network; ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes; GLP-1=Glucagon-like peptide-1; UTI=urinary tract infection; DKA=diabetic ketoacidosis

References

  1. Boehringer Ingelheim Limited. Jardiance SPC. February 2019. www.medicines.org.uk/emc/
  2. Häring HU et al. Diabetes Care 2014; 37: 1650–1659.
  3. Häring HU et al. Diabetes Care 2013; 36: 3396–3404.
  4. Ridderstråle M et al. Lancet Diabetes Endocrinol 2014; 2 (9): 691–700.
  5. Zinman B et al. N Engl J Med 2015; 373 (22): 2117–2128.
  6. Roden M et al. Lancet Diabetes Endocrinol 2013; 1 (3): 208–219.
  7. Inzucchi S et al. Oral presentation A18 and poster P187, presented at: Diabetes UK Professional Conference, March 2018, London, UK. 
  8. Fitchett D et al. Eur Heart J 2018; 39 (5): 363–370.
  9. NICE. Canagliflozin, dapagliflozin and empagliflozin as monotherapies for treating type 2 diabetes. Technology Appraisal 390. NICE, 2016. Available at: www.nice.org.uk/guidance/ta390
  10. NICE. Empagliflozin in combination therapy for treating type 2 diabetes. Technology Appraisal 336. NICE, 2015. Available at: www.nice.org.uk/ta336
  11. SIGN. Pharmacological management of glycaemic control in people with type 2 diabetes. SIGN 154. SIGN, 2017. www.sign.ac.uk/sign-116-and-154-diabetes.html
  12. Davies M et al. Diabetologia 2018; 61 (12): 2461–2498.
  13. MIMS website. MIMS online. www.mims.co.uk (accessed 22 March 2019).
  14. MHRA. SGLT2 inhibitors: updated advice on increased risk of lower-limb amputation (mainly toes). Drug Safety Update March 2017, vol 10, issue 8: 1.

 

PC-UK-100106 (V1)

Date of preparation: April 2019